Elevated cyclooxygenase-2 expression is associated with histological grade in invasive ductal breast carcinoma.
ABSTRACT The aim of this study was to evaluate the expression of cyclooxygenase-2 in human breast cancer using immunohistochemistry and to determine whether the expression of cyclooxygenase-2 is associated with clinicopathological factors in invasive ductal breast carcinoma.
Cyclooxygenase-2 expression was investigated by immunohistochemistry in 30 invasive ductal breast carcinoma specimens and relationships between cyclooxygenase-2 expression and age, histological grade, histological type, nodal status, and hormone receptor status were evaluated.
Cyclooxygenase-2 expression was found in 56.7% of the tumor samples and was related to histological grade (P<0.01) and histological type (P<0.001).
Our results suggest that cyclooxygenase-2 expression has an important role in tumor differentiation in invasive ductal breast carcinoma.
[show abstract] [hide abstract]
ABSTRACT: Experiments in animals and two epidemiologic studies in humans suggest that aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) may be protective against colon cancer. We tested this hypothesis in a prospective mortality study of 662,424 adults who provided information in 1982 on the frequency and duration of their aspirin use. Death rates from colon cancer were measured through 1988. The possible influence of other risk factors for colon cancer was examined in multivariate analyses for 598 case patients and 3058 matched control subjects drawn from the cohort. Death rates from colon cancer decreased with more frequent aspirin use in both men and women. The relative risk among persons who used aspirin 16 or more times per month for at least one year was 0.60 in men (95 percent confidence interval, 0.40 to 0.89) and 0.58 in women (95 percent confidence interval, 0.37 to 0.90). The risk estimates were unaffected when we excluded persons who reported at entry into the study that they had cancer, heart disease, stroke, or another condition that might influence both their aspirin use and their mortality. Adjustment for dietary factors, obesity, physical activity, and family history did not alter the findings significantly. No association was found between the use of acetaminophen and the risk of colon cancer. Regular aspirin use at low doses may reduce the risk of fatal colon cancer. Whether this is due to a direct effect of aspirin, perhaps mediated by the inhibition of prostaglandin synthesis, or to other factors indirectly associated with aspirin use is unclear.New England Journal of Medicine 01/1992; 325(23):1593-6. · 53.30 Impact Factor
Article: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2).[show abstract] [hide abstract]
ABSTRACT: Two cyclooxygenase isozymes catalyze conversion of arachidonic acid to prostaglandin H2: constitutive COX-1 and inducible COX-2. To assess the role of COX-2 in colorectal tumorigenisis, we determined the effects of COX-2 gene (Ptgs2) knockouts and a novel COX-2 inhibitor on Apc delta716 knockout mice, a model of human familial adenomatous polyposis. A Ptgs2 null mutation reduced the number and size of the intestinal polyps dramatically. Furthermore, treating Apc delta716 mice with a novel COX-2 inhibitor reduced the polyp number more significantly than with sulindac, which inhibits both isoenzymes. These results provide direct genetic evidence that COX-2 plays a key role in tumorigenesis and indicate that COX-2-selective inhibitors can be a novel class of therapeutic agents for colorectal polyposis and cancer.Cell 12/1996; 87(5):803-9. · 32.40 Impact Factor
Article: The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis.[show abstract] [hide abstract]
ABSTRACT: Epidemiological and animal studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia. We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam. Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam. To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.Cancer Research 09/2000; 60(18):5040-4. · 7.86 Impact Factor
Purpose: The aim of this study was to evaluate
the expression of cyclooxygenase-2 in human
breast cancer using immunohistochemistry and to
determine whether the expression of cyclooxyge-
nase-2 is associated with clinicopathological fac-
tors in invasive ductal breast carcinoma.
Methods: Cyclooxygenase-2 expression was
investigated by immunohistochemistry in 30 inva-
sive ductal breast carcinoma specimens and rela-
tionships between cyclooxygenase-2 expression
and age, histological grade, histological type,
nodal status, and hormone receptor status were
Results: Cyclooxygenase-2 expression was
found in 56.7% of the tumor samples and was relat-
ed to histological grade (P＜0.01) and histological
cyclooxygenase-2 expression has an important
role in tumor differentiation in invasive ductal
results suggest that
Key words: cyclooxygenase-2, breast carcinoma,
Epidemiological studies have suggested the
chemopreventive effects of non-steroidal anti-inflam-
matory drugs (NSAIDs) in colorectal cancer1,2,3.
Cyclooxygenase (COX) is the major cellular target of
NSAIDs and regulates
prostaglandins. Two isoforms of COX are recognized;
COX-1, the constitutively expressed isoform, and
COX-2, the inducible type, which is induced by proin-
flammatory cytokines, growth factors, and mitogens4.
Numerous studies have emphasized that COX-2
plays an important role in the prevention of colon can-
cer5,6,7,8, and may be involved in tumorigenesis of the
tumors13,14,15. More recent studies indicate that COX-2
contributes to cell proliferation, mediates inhibitory
effects on apoptosis, modulates the production of sev-
eral proangiogenic factors, and increases cell inva-
In early studies, the effects of NSAIDs on breast can-
cer risk were underestimated19. In contrast, analysis of
prospective data has recently indicated the protective
effects of the regular aspirin, ibuprofen and other
NSAIDs against the development of breast can-
cer20,21. Animal studies have demonstrated that selec-
tive COX-2 inhibitors can reduce tumor incidence and
In human breast cancer, several studies have
shown that expression of COX-2 mRNA and protein is
elevated, and COX-2 has been implicated the patho-
genesis of the disease13,24,25,26. Ristimäki et al. have
studied large numbers of breast tumor samples and
showed a significant correlation between elevated
COX-2 protein expression and a number of clinico-
the synthesis of
and other solid
Elevated cyclooxygenase-2 expression is associated with histological grade in
invasive ductal breast carcinoma
Emiko Takeshita, Takayuki Osanai, Tetsuro Higuchi, Labile Togba Soumaoro and Kenichi Sugihara
Department of Surgical Oncology, Graduate School of Medicine, Tokyo Medical and Dental University
J Med Dent Sci 2005; 52: 189–193
Corresponding Author: Kenichi Sugihara
Department of Surgical Oncology, Graduate School of Medicine,
Tokyo Medical and Dental University
1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Tel: +81-3-5803-5261 Fax: +81-3-5803-0139
Received May 6; Accepted June 10, 2005
pathological variables, including tumor stage, hor-
mone receptor status and HER-227. However, other
groups have reported that COX-2 expression is not
associated with some of these factors28,29,30. Thus, the
relationships between COX-2 expression and tumor
characteristics remain uncertain. The aim of this
study was to assess whether expression of COX-2 pro-
tein is associated with clinicopathological factors in
invasive ductal breast carcinoma by immunohisto-
Materials and Methods
Surgical specimens from 30 patients diagnosed as
having primary invasive ductal breast carcinoma and
operated on between 1999 and 2001 at the
Department of Surgical Oncology of Tokyo Medical and
Dental University were studied. The Human Subjects
Committee at Tokyo Medical and Dental University
approved the research protocol. All patients gave writ-
ten consent to participate in the study.
For immunohistochemical examination of COX-2,
we used a universal immunoenzyme polymer method.
Formalin-fixed, paraffin-embedded specimens were
serially sectioned at a thickness of 3 Òm, placed onto
MAS-coating slides. Specimens were deparaffinized,
rehydrated, and antigen was retrieved using an auto-
clave at 121°C for 20 minutes in 10 mM sodium citrate
buffer (pH 6.0), then treated with 3% hydrogen peroxide
in methanol solution at room temperature for 15 min-
utes to quench endogenous peroxidase activity.
Nonspecific reactivity was blocked by treating slides
with 10% normal goat serum for 10 minutes. The pri-
mary antibody used for immunohistochemical staining
was anti-human COX-2
(Cayman Chemical Co., Ann Arbor, MI, USA) at a dilu-
tion of 1:500 and applied overnight at 4°C. Next,
slides were incubated with labeled polymer (N-
Histofine Simple Stain MAX PO MULTI, Nichirei Co.,
Tokyo, JAPAN) for 30 minutes at room temperature.
Sections were incubated in 0.02% 3, 3’-diaminobenzi-
dine tetrahydrochloride (Dojin Chemical Laboratory,
Co., Kumamoto, JAPAN) and 0.06% hydrogen peroxide
in 50mM Tris-Hcl (pH7.6) for 5 minutes. Finally, slides
were counterstained with 1% Meyer’s hematoxylin. A
known COX-2-positive colonic cancer sample was
used as a positive control. As a negative control, tissue
sections were treated with normal mouse IgG serum
instead of primary antibody 31.
Evaluation of COX-2 immunohistochemistry
COX-2 immunohistochemical staining was scored
independently by two investigators (E.T. and T.O.)
who were blinded as to the sample origins. Evaluation
of COX-2 expression was semiquantitatively estimated
by intensity and area of positive cells, modifying the
methods of Ristimäki et al. 27: Negative staining; no
staining or weak diffuse cytoplasmic staining (may
contain stronger intensity in less than 10% of cancer
cells); Elevated staining, moderate to strong granular
cytoplasmic staining in 10-100% of cancer cells.
Association between COX-2 staining and clinico-
pathological factors was then investigated.
Histological grade was assigned according to the
Nottingham modification of the Bloom and Richardson
grading system. The grade was obtained by summing
the scores for tubule formation, nuclear pleomor-
phism, and mitotic count, each of which was given 1, 2,
or 3 points. Grade I invasive carcinomas had 3 or 4
points, grade II neoplasms had 5 to 7 points, and grade
III tumors had 8 or 9 points32. The histological type of
human breast cancer investigated was invasive ductal
carcinoma, which was classified as papillotubular car-
cinoma, solid-tubular carcinoma or scirrhous carcinoma
according to the Japanese Breast Cancer Society cri-
teria33. When combined histological type was
observed, predominant type was selected for evalua-
The correlations between COX-2 expression and
several clinicopathological parameters were analyzed
by Á2test. P values of less than 0.05 were considered
significant. For statistical evaluation, we used the
StatView software package (version 5.0; SAS Institute
Inc., Cary, NC).
Mean patient age was 55 (range, 31-75) years.
Patient characteristics, including histological type, his-
tological grade, hormone receptor status, and nodal
status are shown in Table 1.
E. TAKESHITA et al. J Med Dent Sci190
Elevated COX-2 expression was found in 57% (17
out of 30) of breast cancer samples. Representative
examples of COX-2 expression are shown in Fig. 1 (1a-
b). COX-2 staining was granular and localized pre-
dominantly in the cytoplasm of the tumor cells.
Negative staining was shown in Fig. 1b. In some
tumor samples, enhanced COX-2 staining was
observed in the perinuclear area (Fig. 1c). Staining in
normal-appearing epithelia was of no intensity
(Fig. 1d). Within the same tissue sections, stromal
staining for COX-2 in endothelial cells, lymphocytes,
and fibroblasts was weakly detected adjacent to COX-
2 expressing tumor epithelia (Fig. 1e).
COX-2 Expression and Tumor Characteristics
Elevated expression of COX-2 was more frequent in
high grade tumors (grade III) than in lower grade
tumors (grade I and grade II) (P＜0.01, Table 1).
Histological type (papillotubular and solid-tubular car-
cinoma vs. scirrhous carcinoma) was also associated
with elevated COX-2 expression (P＜0.001, Table 1). All
samples of scirrhous carcinoma showed elevated
COX-2 expression, while 73.3% and 100% of papillo-
tubular and solid-tubular samples were negative. No
significant correlations were observed between COX-2
expression and age, estrogen receptor (ER), proges-
terone receptor (PgR), or lymph node status (Table 1).
In the present study, we found that elevated expres-
sion of COX-2 was associated with higher histological
grade. This suggests that COX-2 has important role in
tumor differentiation in invasive ductal breast carcino-
ma. Elevated COX-2 expression was previously found
to be associated with tumor size and depth in colorec-
tal and gastric cancer34 35and with grade of dysplasia in
colorectal adenoma36. In those studies, however, no
evaluation was conducted on COX-2 expression and
In breast cancer studies, our analyses of correlation
between COX-2 expression and histological factors are
consistent with the results of others27,37,38, but they also
contradict some reports28,30,39,40,41. In a recent study,
191CYCLOOXYGENASE -2 EXPRESSION IN BREAST CARCINOMA
Table 1. Relationships between elevated COX-2 expression and clin-
(COX-2) in samples of invasive ductal breast carcinoma.
COX-2 staining is detected in the cytoplasm of the tumor cells.
Scirrhous carcinoma, grade III shows elevated expression of COX-2
(1a, ×40). Example of negative expression: solid tubular carcinoma,
grade II. (1b, ×40). COX-2 protein is strongly expressed in perinu-
clear area of the tumor cells (1c, ×400). Normal breast epithelia are
shown with negative staining (d, ×200). Immunoreactive COX-2 is
detected in stromal cells surrounding the tumor cells (e, ×200).
Immunohistochemical expression of cyclooxygenase-2
Shim et al. showed that COX-2 expression was
detected in almost all ductal carcinoma in situ speci-
mens, with increased COX-2 staining correlating with
higher nuclear grade42. In the present findings, associ-
ation between lower histological grade (I and II) versus
higher grade (III) was compared to COX-2 expression.
Based on O’Reilly’s description, histological grades I
and II were combined to one category of “well-differ-
entiated” tumors, and only grade III tumors were ana-
lyzed as a separate, single group43. The presence of
significant correlations in our study group may have
resulted from the close relationship between histologi-
cal grade and histological type of invasive ductal carci-
noma; almost all scirrhous carcinoma samples exhibit-
ed elevated COX-2 expression and most scirrhous car-
cinoma belonged to grade III.
According to the classification by the Japanese
Breast Cancer Society, there are three types of invasive
ductal carcinoma and prognosis of patients with papil-
lotubular type is known to be the best, while scirrhous is
the worst33. Elevated COX-2 expression would therefore
be a marker of poor differentiation, and may reflect the
prognosis of invasive ductal carcinoma. Some investi-
gators have reported that elevated COX-2 expression is
associated with a significantly worse disease-free sur-
vival and overall survival, and have evaluated COX-2 as
one of prognostic factors27,44,45.
COX-2 in malignant tumors is thought to be
involved in tumorigenesis. Shattuck-Brandt et al. have
reported that COX-2 expression was observed in both
epithelial and tumor stromal cells46. In our samples,
COX-2 immunoreactivity was detected with weak
intensity in stromal cells surrounding the tumor cells.
Moreover mastopathy and adenosis adjacent to COX-2
positive carcinomas also expressed COX-2 otherwise
mastopathy alone didn’t show COX-2 positivity (data
not shown). This observation supports the notion that
COX-2 in stromal cells acts to promote tumors and
exerts paracrine effects on nearby carcinoma cells47.
One study has emphasized the significant roles of
fibroblasts and endothelial cells in the intestinal polyp
development through COX-2 expression, while little
COX-2 expression was seen in macrophages48. In
contrast, other groups found that COX-2 was
expressed predominantly by macrophages in the stro-
ma47,49. COX-2 expression in breast cancer stromal
cells has not been clarified. One reason may be that it
is difficult to distinguish stromal cells from tumor cells
because of the unique morphology of breast cancer.
The potential value of COX inhibitors for breast can-
cer is currently under examination50. However, it is not
known which group of patients could gain the most ben-
efit from COX inhibitors. Our results showing the posi-
tive correlation between elevated COX-2 and higher his-
tological grade suggest that COX-2 inhibitors have a
potential therapeutic effect on grade III scirrhous inva-
sive ductal breast carcinoma.
We thank Ms. Yoko Takagi for valuable technical
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193CYCLOOXYGENASE -2 EXPRESSION IN BREAST CARCINOMA